Viruses belonging to the Herpesviridae family cause various infectious diseases in human and animals. For example, it is known that varicella zoster virus (VZV) causes varicella and herpes zoster, and herpes simplex viruses of types 1 and 2 (HSV-1 and HSV-2) cause infections such as herpes labialis and genital herpes, respectively. In recent years, additionally, infectious diseases caused by herpesviruses such as cytomegalovirus (CMV), EB virus (Epstein-Barr virus; EBV), and human herpesviruses 6, 7 and 8 have been elucidated.
Currently, pharmaceutical drugs of nucleic acid series, such as acyclovir (ACV) and its prodrugs varacyclovir (VCV) and fancyclovir (FCV) are used as drugs against herpesviruses, such as VZV and HSV. These pharmaceutical drugs of nucleic acid series are mono-phosphorylated into nucleoside monophosphates by viral thymidine kinase encoded by VZV and HSV and are subsequently converted into triphosphate compounds by cellular enzymes. Finally, the tri-phosphorylated nucleoside analogues are incorporated during the replication of the viral genomes by herpesvirus DNA polymerase, to suppress the extension reaction of the viral DNA chains. Since the reaction mechanism of the existing anti-herpesvirus agents is based on the effect of the “competitive inhibition” toward deoxynucleoside triphosphate, as described above, it is necessary to use these drugs at a high concentration for the exertion of their antiviral effects. In a current state, actually, these anti-herpes drugs of nucleic acid series are clinically administered at a dose as high as several hundreds in mg to several grams per day. Since pharmaceutical drugs of nucleic acid series are readily incorporated into the genome DNA of a host via the host DNA polymerase, further, the mutagenicity thereof draws concerns.
On the other hand, lately, several pharmaceutical drugs of non-nucleic acid series and with anti-herpesvirus activity have been reported. For example, it is disclosed an amide or sulfonamide derivative suppressing the HSV helicase/primase enzyme complex to show anti-HSV-1 activity and anti-CMV activity, as represented by the following formula (G), where the N atom is substituted with thiazolylphenylcarbamoylmethyl group or the like (the pamphlet of the International Publication WO 97/24343). However, the anti-VZV activity of these compounds is not specifically disclosed therein. (In the formula, R is hydrogen, a lower alkyl, amino, a lower alkylamino or the like; R2 is hydrogen or a lower alkyl; Q may not exist or when it exists, Q represents methylene; R3 is hydrogen, a lower alkyl or the like; R4 is an unsubstituted or substituted phenyl (lower) alkyl, 1-indanyl, 2-indanyl, (lower cycloalkyl)-(lower alkyl), (Het)-(a lower alkyl) or the like; R5 is phenylsulfonyl, 1- or 2-naphthylsulfonyl, (Het)-sulfonyl, (unsubstituted or substituted phenyl)-Y—(CH2)nC(O), (Het)-(CH2)nC(O) or the like wherein Y is O or S and n is 0, 1 or 2; see the Reference 1 for details.)
It is also disclosed an amide or sulfonamide derivative with anti-HSV-1 activity and anti-CMV activity as represented by the following formula (H) wherein the N atom is substituted with thiazolylphenylcarbamoylmethyl group (the pamphlet of the International Publication WO 00/29399). However, the anti-VZV activity of these compounds is not specifically disclosed therein. (In the formula, R1 is NH2; R2 is H; R3 is H; R4 is CH2Ph, CH2-(4-pyridyl), CH2-cyclohexyl or the like; and R5 is CO— (substituted phenyl), CO— (unsubstituted or substituted hetero ring) or the like; see the Publication for details.)
The present inventors previously found an amide compound substituted with thiazolylphenylcarbamoylmethyl group and with great anti-VZV activity, as represented by the following formula where the N atom of the amide group is substituted directly with an aromatic group aryl or heteroaryl group, or the salt thereof. Thus, the inventors filed a patent application (the pamphlet of the International Publication WO 02/38554). (In the formula, R1 and R2 represent —H, -lower alkyl, —NRaRb, or the like; A represents -aryl which may or may not have a substituent(s) or -heteroaryl which may or may not have a substituent(s) or the like; R3 represents -aryl which may or may not have a substituent(s) or -hetero ring which may or may not have a substituent(s) or the like; X represents CO or SO2; see the Publication for details).
Still now, the creation of an anti-herpesvirus drug with a satisfactory anti-herpesvirus activity and of non-nucleic acid series is strongly desired, which is highly safe at a low dose and suitable for oral dosing.